Individuals with major depressive disorder (MDD) have an increased heart rate — a finding that may have the potential to identify individuals at risk for the disorder and predict treatment response, early research suggests.

Using the rapid-action of the novel antidepressant ketamine and the latest wearable 24-hour electrocardiogram (ECG) technology, investigators found that heart rate could distinguish MDD patients from healthy individuals.

The researchers’ goal was to determine whether heart rate and HRV could be used as trait markers to distinguish MDD patients from healthy individuals and, via the use of ketamine, whether they can also act as state markers for depression.

For the study, 16 treatment-resistant patients with MDD and 16 age- and sex-matched healthy controls wore a portable electrocardiogram (ECG) device for 4 consecutive days and 3 nights. Heart rate and HRV data was subsequently averaged to obtain a 24-hour ECG.

Participants then received a single infusion of intravenous ketamine for 40 minutes. After waiting for 1 hour, the patients resumed ECG recording for an additional 4 days, with changes in mood assessed using the Hamilton Rating Scale for Depression (HAM-D).

Results showed that compared with the control group, patients with MDD had a significantly higher 24-hour heart rate (P < .001) and a significantly lower HRV, as measured by the root mean square of successive differences (P < .001).

The investigators also found a reduction in heart rate amplitude, indicating “significant blunting of circadian rhythm variation throughout the day and less recovery at night.”

90% Accuracy

Harmonic and binary regression showed that heart rate was able to identify those with MDD vs the control group, particularly using nighttime readings, with 90.6% accuracy. The data correctly identified 14 (87.5%) patients and 15 (93.8%) members of the control group.

Following treatment, heart rate decreased significantly among the MDD group (P < .001), but there was no significant change in HRV (P = .295).

There was a significant positive association between baseline heart rate and response to treatment on the HAM-D (r = .55, P = .046), which suggested better outcomes in patients with a higher heart rate.

Interestingly, while heart rate was positively correlated with depression severity before treatment (r = .59, P = .03), this relationship disappeared following treatment (r = –0.04, P = .90), suggesting heart rate changes were not likened to depression states.

While heart rate levels may be useful as a trait marker and, potentially, for prediciting response to antidepressant treatment, they did not show potential as a state marker, the investigators note.

They suggest that while the results need to be confirmed in longitudinal studies, approval of a ketamine nasal spray “may open up new avenues to conceive treatment paradigms, as explored in this study.”

However, “this is a small proof-of-concept study,” the investigators acknowledge. They also point out that only six of the patients with MDD had a reduction in HAM-D scores of at least 30% in response to treatment.

Future Research Plans

Schiweck told Medscape Medical News her team was able to identify differences in heart rate and HRV in MDD patients that were not observed in other studies because portable at-home devices allowed them to monitor heart rate continuously over days.

The use of ketamine may also have been advantageous because the Netherlands Study of Depression and Anxiety (NESDA), which was published in 2010, clearly showed that “traditional antidepressants,” in particular tricyclic antidepressants, have a strong influence on heart rate and HRV, Schiweck said.

The team next wants to replicate their study in patients who take non-ketamine antidepressants and then remit, because most of the recent studies “just assess patients who are remitted and patients who are currently depressed, but it’s a cross-sectional study design,” said Schiweck.

“If we can follow up the same patients over time then we might really know if it is possible to use heart rate as a state marker for depression,” she added. “That‘s what we tried to do with ketamine, but our study was very, very small.”

She noted that the investigators would also like to assess individuals who are “very stressed” and may show some depressive symptoms but don’t yet have a diagnosis of depression.

Mind–Body Link

Commenting on the findings for Medscape Medical News, Brenda W.J.H. Penninx, MD, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam, the Netherlands, said the concept of higher heart rate and lower HRV in depression “is indicative of more sympathetic drive and less parasympathetic drive of the autonomic nervous system.”

“That fits with the overall thought that depression is a state with more continuous exposure to stress overactivation of the body, which can be reflected in the HPA axis, leading to higher levels of cortisol stress hormone. But it can also be reflected in the parasympathetic and sympathetic activation of the autonomic nervous system,” she said.

Penninx, who was also the principal investigator of the NESDA study, was not involved with the current research.

She noted that the NESDA study showed that when patients with depressive disorder are compared with a healthy controls group, they have a higher heart rate and lower HRV. “But if we then divide people into medicated and nonmedicated people…then we see that these deviations are only seen in people using medication,” she added.

“Our findings indicate that at least the use of antidepressants is having quite a large impact on autonomic nervous system dysregulation,” Penninx said. The difference with the current study, she pointed out, is that “it examines the problem over a completely different time scale.”

Although this offers advantages, the current study did not have the large patient numbers that were included in the NESDA study and “they were not clearly able to distinguish the effect of disease from medication,” noted Penninx.

In addition, this is not an easy area to investigate because there are multiple factors that can mitigate results, including the psychiatric state of the patient, use of medications for both mental illness and cardiometabolic disease, a patient’s age, and his or her gender.

Still, the study clearly illustrates the importance of the interplay between mental health and somatic health and that there is “a very clear indication that we don‘t need to separate those,” Penninx said.

The study was funded by a TGO-IWT Grant from Belgium. The study authors and Penninx have disclosed no relevant financial relationships.

33rd European College of Neuropsychopharmacology (ECNP) Congress. Abstract P257. Presented September 15, 2020.